By: Helen (Bomin) Kim
CAUSES

Introduction:

Schizophrenia is not a monogenic (one gene causing the disease) disease, hence making the determination of the causal gene difficult. However, close examination of the disease for a long time have brought scientists to narrow down the search somewhat to several genes in combination with environmental factors that contribute to the disease phenotype, endophenotype and genotype. Other factors contributing to this drawback are the variability of the diagnostic phenotype as well as the interactions of the underlying genes [2].

Genetic Factors:

Fig. 2 Chromosome 4 and 6 of the human genome. [18]chromo4.pngchromo6.png
Multiple studies showed that depending on the ethnic background of the patient, interaction between candidate genes, and the location of the causal genes, the gene product responsible for the disease onset and symptoms vary [2]. Through meta-analyses, different groups found that Costa Rican schizophrenic patients have linkages in chromosome 5q, while Finnish patients showed linkage to chromosomes 1q, 4q, 9q and Xp. Another group that studied African-American schizophrenic patients showed regions of chromosomes 4, 6, 8 and 11 to contain the candidate genes. PAARTNERS, Project among African-Americans to Explore Risks for Schizophrenia have studied a huge group of patients, proband samples obtained from schizophrenic and schizophrenia spectrum disorder patients diagnosed through DSM-IV diagnostic criteria [1].

PAARTNERS:
Wiener et al., chose African-American schizophrenic patients and their related affected family members as ideal test subjects. The genetic background of this population can be traced back to both Africans as well as the European population, allowing for if a difference in the causal gene was found, one can deduce that the environment must also be playing a role. Regardless, the focus of this paper was on the regions of the chromosome and performing fine mapping of the chromosome [12]. The patients and their related family members were required to fall under the following criteria, ASP (Affected Sibling Pair), TRIO (either two parents or for every unavailable parent, an additional sibling), and MP (multiplex, one or more affected first degree relatives with at least 8 affected first to 4th degree relatives) [12].
Diagnostic criteria DSM-IV was used to diagnose patients and choose a large group of patients that fell under schizophrenia (SZ) or schizoaffective disorders (SZA). Genome scan was performed for detection of the regions on chromosomes that contained the possible genes responsible. Endophenotypes were observed using multipoint Quantitative Trait Locus (QTL)
Fig. 1 Wiener et al., 2009; family criteria [1]wiener_et_al_2009.pngfor linkage analyses. Targeting European ancestry lines pointed the direction towards the common gene, Neuregulin 1 (Nrg1). Genome wide linkage analysis of the patients DNA samples showed highest linkage in chromosome 11. However, overlapping from other European studies and the samples from the Veterans Affairs Cooperative Study are regions on chromosomes 4 and 6; where the candidate genes NRG1 and NOTCH4 have been studied to reside [1].

NOTCH4:
This gene was found to reside in the region of the chromosome 6p, while PAARTNERS was discussed above for theorizing this gene to be one of the many genes involved in triggering the onset of Schizophrenia in patients, other groups have also come to conclude this region of the chromosome to contain the causal gene. In 2000, this gene was first found to be associated in a British population of schizophrenic patients [10]. Luo et al., studied African-American groups and European-American groups that showed poor association of the NOTCH4 gene [8], this inability to replicate finding NOTCH4 allelic association may be due to the ethnical differences between different populations [10].
Close inspection of the gene have showed allelic variation of this gene in schizophrenic patients. It was associated with normal frontal lobe cognitive functionality as well as the volume of this region [11]. Wassink et al., showed that this gene had a CTG exonic polymorphism, affecting the cognitive function and the morphology of the frontal lobe see in these patients. The affected groups were compared to a control group to eliminate the possibility of generalized effect of this gene in normal healthy people as opposed to being exclusive in schizophrenic patients [11]. In 2001, it was determined that NOTCH is a receptor when activated translocates into the nucleus of the cell and subsequently activates the transcription of genes required in normal neuronal development [13].
"Angiolab Illustration of Notch Receptor Mechanism - [15]notch_receptor.jpg
However, when German and Palestinian-Arab population was used as a test sample, the same association of the NOTCH4 gene with schizophrenia was not seen [6]. This can be explained due to the fact that NOTCH4 locus is found within in the MHC region of the chromosome 6p, where it contains multiple genes. The interaction between these genes have been found to be extremely complicated in humans thus making it difficult to know whether NOTCH4 is in fact the correct causal gene or some other gene found in the same region. For instance, the gene TNXB found in the same region as NOTCH4 is an important extracellular matrix protein known to be important in the central nervous system during embryongenesis, as such, further studies must be done on this MHC region of chromosome 6 [10].


NRG1:
The introduction of this gene behind the onset of schizophrenia introduces the concept of interaction of gene and environment giving rise to the phenotype. The environmental stimulus involved in triggering this gene is cannabinoids. It has been shown that those showing schizophrenic symptoms already have increased psychosis with the use of cannabinoids. However, those who have yet to show symptoms but carry the susceptible gene show increased risk in developing the disease with the use of this drug [4]. Boucher et al., analyzed heterozygotic mice for NRG1 gene upon exposure to cannabinoids. These heterozygotic mice show schizophrenic phenotypes when exposed to ∆9-tetrahydrocannabinol (THC = a psychoactive constituent of cannabis). Exposure to THC showed an increased expression of c-Fos in the CNS [3]. A closer look at this gene showed that the product is a Nrg1 protein, a ligand that effects neurodevelopmental processes hence showing schizophrenic symptoms in these mice [5]. Heterozygosity for this gene showed schizophrenic symptoms in mice [7, 9], as such, these heterozygotic mice were used to determine whether normal healthy mice with this gene show susceptibility to developing the disease upon exposure to cannabinoids [4].
The effect of Neuregulin 1 gene comes in two-fold by the environmental stimulus cannabinoids. It has been shown that those showing schizophrenic symptoms already have increased psychosis with the use of cannabinoids. However, those do not yet to show symptoms but inherited the susceptible gene show increased risk in developing the disease with the abuse of this drug [4].Fig. 4. THC structure[16]thc.jpg
Heterozygosity for this gene showed schizophrenic symptoms in mice with this genotype [7, 9]. As such, these heterozygotic mice were used to determine whether normal healthy mice with this gene show susceptibility to developing the disease upon exposure to cannabinoids.


Environmental Influence:

Fig. 5 interaction of genes and environment giving rise to phenotype (vice versa). [17]gep.png

Many research groups have tried to pinpoint the causal gene for this disease, while many genes have been discovered, it has been shown that this disorder can also arise from environmental stimuli.

As discussed with the Nrg1 gene, it was shown that not only the presence of genetic defect triggers the disease onset, but the environmental stimuli increase the possibility of susceptible genes to become active.

Many environmental factors have been shown to increase the risk of developing the disease later on in life. Such factors are maternal diabetes, season, prenatal maternal stress, location or birth as well as socioeconomic status. While each factor can increase the risk on their own, a combination of these factors with the susceptible genes increases the likelihood of developing the disease. Studies have shown that these stimuli trigger the susceptible genes to get “turned on” and thus begin the process of showing phenotypes of the disease. On the other hand, it is possible to reduce the risk of this susceptibility if the child is kept under minimal stress, and reduced exposure to toxins [14].


  1. Aliyu, M. H., Calkins, M. E., Swanson, C. L., Lyons, P. D., Savage, R. M., May, R., Wiener, H., Devlin, B., Nimgaonkar, V. L., Ragland, J. D., Gur, R. E., Gur, R. C., Bradford, L. D., Edwards, N., Kwentus, J., McEvoy, J. P., Santos, A. B., McCleod-Bryant, S., Tennison, C., Go, R. C. P. 2006. Projects among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods. Schizophrenia research, 87: 32-44.
  2. Bertolino, A., Blasi, G. 2009. The genetics of schizophrenia. Neuroscience, 164: 288-299
  3. Boucher, A. A., Hunt, G. E., Karl, T., Micheau, J., McGregor, I. S., Arnold, J. C. 2007. Heterozygous neuregulin 1 mice display greater baseline and delta9-tetrahydrocannabinol-induced c-fos expression. Neuroscience, 149: 861-870
  4. Boucher, A. A., Hunt, G. E., Micheau, J., Huang, X., McGregor, I. S., Karl, T., Arnold, J. C. 2011. The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. International journal of Neuropsychopharmacology, 14: 631-643.
  5. Falls, D.L. 2003. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res, 284:14–30.
  6. Ivo, R., Schulze, T. G., Schumacher, J., Kesper, K., Muller, D. J., Kremer, I., Dobrusin, M., Mujaheed, M., Murad, I., Blanaru, M., Bannoura, I., Reshef, A., Bachner-Melman, R., Ebstein, R. P., Propping, P., Belmaker, R. H., Maier, W., Rietschel, M., Nothen, M. M., Cichon, S. 2006. No evidence for association between NOTCH4 and schizophrenia in a large family-based and case-control association analysis. Psychiatric genetics, 16: 197-203.
  7. Karl, T., Duffy, L., Scimone, A., Harvey, R.P., Schofield, P.R. 2007. Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav, in press.
  8. Luo, X., Klempan TA, Lappalainen J, Rosenheck RA, Charney DS, Erdos J, van Kammen DP, Kranzler HR, Kennedy JL, Gelernter J. 2004. NOTCH4 gene haplotype is associated with schizophrenia in African Americans. Biol Psychiatry 55:112–117.
  9. Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T.T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V.G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R.P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. 2002. Neuregulin 1 and susceptibility to schizophrenia. American Journal Hum Genet, 71: 877–892.
  10. Wang, Z., Wei, J., Zhang, X., Guo, Y., Xu, Q., Liu, S., Shi, J., Yu, Y., Ju, G., Li, Y., Shen, Y. 2006. A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia. American Journal of medical genetics part B (neuropsychiatric genetics), 141B: 902-906.
  11. Wassink, T. H., Nopoulos, P., Pietila, J., Crowe, R. R., Andreasen, N. C. 2003. NOTCH4 and the frontal lobe in schizophrenia. American Journal of Medican genetics Part B, 118B: 1-7
  12. Wiener, H. W., Klei, L., Irvin, M. D., Perry, R. T., Aliyu, M. H., Allen, T. B., Bradford, L. D., Calkins, M. E., Devlin, B., Edwards, N., Gur, R. E., Gur, R. C., Kwentus, J., Lyons, P. D., McEvoy, J. P., Nasrallah, H. A., Nimgaonkar, V. L., O’Jile, J., Santos, A. B., Savage, R. M., Go, R. C. P. 2009. Linkage Analysis of schizophrenia in African-American Families. Schizophrenia Research, 109: 70-79.
  13. Fortini, M.E. 2001. Notch and presenilin: A proteolytic mechanism emerges. Curr Opin Cell Biol 13:627–634.
  14. King, S., St-Hilaire, A., Heidkamp, D. 2010. Prenatal factors in schizophrenia. Curr directions in psychological science, 19(4): 209-213.
  15. Angio Lab Research - figure retrieved March 28th, 2012. http://www.angiolab.de/research/vascular_dev.htm
  16. Kind Green Buds - figure retrieved March 28th, 2012. http://www.kindgreenbuds.com/cannabis-grow-bible/thc.html
  17. Psychology Today - figure retrieved March 28th, 2012. http://www.psychologytoday.com/blog/anxiety-files/201003/misunderstanding-evolutionary-theory
  18. DNARSS, genetics, genomics, proteonomics - figure retrieved March 28th, 2012. http://www.dnarss.com/Chromosome_4.html